A method for producing a preparation through melt extrusion of a mixture of a drug and a polymer under heating has recently attracted attentions.
For example, a solid dispersion obtained by solidifying a poorly water-soluble drug and a polymer through hot-melt extrusion improves bioavailability of the drug because the drug is molecularly dispersed in an amorphous form in the polymer carrier and the apparent solubility of the drug shows a marked increase. Further, the hot-melt extrusion can avoid using a solvent so that it has various advantages. For example, the hot-melt extrusion can be applied to a drug not stable in water, is safe and environmentally friendly because of unnecessity of solvent recovery, can save energy spent for the solvent recovery, and provides a working environment with improved safety. Still further, differing from conventional batch production, this method permits continuous production so that it has attracted attentions also from the standpoint of hourly productivity and consumption energy.
One example of the polymers to be used for hot-melt extrusion is hypromellose acetate succinate (which may hereinafter be called “HPMCAS”) which is obtained by introducing four substituents in total in a cellulose skeleton, more specifically, introducing two substituents, that is, a methoxy group (—OCH3) and a hydroxypropoxy group (—OC3H6OH) to form an ether structure and two substituents, that is, an acetyl group (—COCH3) and a succinyl group (—COC2H4COOH) to form an ester structure.
The content of each of the substituents of HPMCAS listed in the Japanese Pharmacopoeia 16th Edition is specified as follows (the Japanese Pharmacopoeia 16th Edition, Supplement I, Official Monographs, “Hypromellose Acetate Succinate”).
TABLE 1Molar substitutionContent (weight %)(MS)*1Methoxy group12.0 to 28.0 0.73 to 2.83Hydroxypropoxy group4.0 to 23.00.10 to 1.90Acetyl group2.0 to 16.00.09 to 2.30Succinyl group4.0 to 28.00.08 to 1.78*1: The term “molar substitution” means an average number of moles of respective group added per glucose ring unit of cellulose.
As a solid dispersion comprising HPMCAS, there is a report on, for example, a solid dispersion composition obtained through hot-melt extrusion of a preliminary mixture obtained by adding water to HPMCAS (commercially available AS-LF having a molar substitution of from 0.16 to 0.35), where an addition of water decreases the glass transition temperature or softening temperature of the HPMCAS or poorly water-soluble drug (WO 2003/077827).
Further, there are proposed a method for producing a preparation through hot-melt extrusion of posaconazole which is a poorly water-soluble drug and HPMCAS (commercially available AS-MF and AS-MG, each having a molar substitution of from 0.15 to 0.34) (Japanese Phase Publication No. 2011-516612T of WO 2009/129300); and a method for producing a preparation through hot-melt extrusion of CETP (cholesteryl ester transfer protein) inhibitor, which is a poorly water-soluble lipid inhibitor, and HPMCAS (commercially available AS-MF having a molar substitution of from 0.15 to 0.34) (Japanese Phase Publication No. 2005-523895T of WO 2003/063832).
Further, there is proposed a method for spray-drying a solid dispersion composition comprising a poorly water-soluble drug and HPMCAS having a hydroxypropoxy molar substitution of 0.25, a succinyl molar substitution of 0.02 or more, an acetyl molar substitution of 0.65 or more, a total molar substitution of the acetyl and succinyl groups of 0.85 or more, and a glass transition temperature of from 131 to 146° C. at 0% RH (Japanese Phase Publication No. 2008-501009T of WO 2005/115330). There is also proposed a method for spray-drying a solid dispersion composition comprising a poorly water-soluble drug and HPMCAS having a hydroxypropoxy molar substitution of not more than 0.21, a methoxy molar substitution of not more than 1.45, and a total molar substitution of the acetyl and succinyl groups of not less than 1.25 (WO2011/159626).